Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death in the United States, accounting for 30,000 deaths yearly in the US1. Despite great efforts to improve treatment for patients with pancreatic cancer, limited progress has been made2, 3. Although much research has been conducted to develop improved systemic therapies for pancreatic cancer, gemcitabine as a single agent given postoperatively remains the current standard of care. Combinations with other chemotherapeutic drugs or biological agents given as a palliative setting for unresectable pancreatic cancer or adjuvant setting following resection have resulted in limited improvement4-6. The 5 year survival of patients with pancreatic cancer, despite numerous phase 3 trials, remains less than 5% after resection7-10. The majority of patients will present with either local or systemic recurrence within 2 years following resection and postoperative adjuvant chemotherapy7-9. Currently, the most effective single agent gemcitabine achieves an improved 1-year survival rate from 16 to 19%. The addition of Tarceva® (erlotinib) in a randomized study added a median of 11 days to overall survival11, 12. This limitation of conventional treatment is due to the profound resistance of PDAC cells towards anti-cancer drugs emerging from the efficient protection against chemotherapeutic drugs13, 14. Therefore, it is imperative to develop new therapeutic strategies for this devastating disease.
To overcome the current treatment obstacles, KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) has been appreciated as a therapeutic target in pancreatic cancer (PC). However, direct targeting KRAS or mutant forms of KRAS which role is well established in pancreatic carcinogenesis has failed in the clinic, assumed to be a undruggable target15. It also indicates that there is another mechanism underlying uniformly regardless of KRAS mutations; BxPC3 harbors wild-type KRAS, whereas other PDAC cell lines harbor mutated KRAS.
Short RNAs targeting to promoter regions of certain genes upregulates the expression at the transcriptional level without altering the genome in human cells, which is termed RNA activation (RNAa/saRNA)16, 17. Contrary to the antagonism of a specific target genes offered by siRNA, the activation of molecular targets is also crucial to control cancer gene expression effectively by the gain of function. The first saRNA targeting non-coding regulatory regions in gene promoters are E-cadherin, p21 and VEGF promoter16. In liver cancer, Reebye et. al. described that saRNA targeting CCAAT/enhancer-binding protein-α (C/EBPα), a transcriptional factor and a leucine zipper protein known to upregulate known to upregulate p21 which is an inhibitor of cell proliferation18, decreases cell proliferation in HepG2 cells. In an in vivo cirrhotic model, intravenous injection of C/EBPα-saRNA decreased tumor burden18. The loss of the KDM6B gene encoding a histone demethylase, another tumor suppressor gene, inhibits transcriptional activation and enhances aggressiveness through downregulation of C/EBPα19. C/EBPα is silenced epigenetically by histone deacetylation and DNA methylation20 in pancreatic cancer.
Aptamers identified using the Systematic Evolution of Ligands by EXponential enrichment (SELEX) as an in vitro selection strategy can adopt complex structures to bind targets with high affinities and specificities21, 22. Aptamers can be selected to recognize a wide variety of targets from small molecules to proteins and nucleic acids in cultured cells and whole organisms23-28. Due to the features of folding back into their natural conformation after denaturation, aptamers may keep their structures stably in the reducing condition29. RNA aptamers offer significant advantages compared to antibodies29. There is a need in the art for up-to-date therapeutic strategies and accurate delivery of therapeutics are imperative. Provided herein are compositions and methods addressing these and other needs in the art.